Process for the preparation of 17beta-oxygenated-delta5(10), 9(11)-estradiene-3-one



United States Patent The invention relates to novel estradienes having the k m (I.

wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms. The invention further relates to novel processes for the preparation of said estradienes and the intermediates thereof.

The estradienes of Formula I have interesting pharmacological properties, and are particularly useful as anabolisants. The said estradienes are also useful intermediates for the preparation of A -estradiene-11,9- ol-3-one and its esters which are used to prepare estradiol by isomerization as disclosed in the commonly-assigned, 'copending U.S. application Serial No. 57,136, filed September 20, 1960.

It is an object of the invention to provide the novel steroids, A -estradiene-17fi-ol-3-one and its esters.

It is another object of the invention to provide novel processes for the preparation of the novel estradienes of Formula I.

It is an additional object of the invention, to provide vnovel intermediates for the novel estradienes of Formula I.

It is a further object of the invention to provide an improved process for the preparation of A -estradiene- ;l7 3-ol-3-one and its esters.

These and other objects and advantages of the invention will become obvious from the following detailed description. v

' The novel compounds of the invention have the formula 3,085,099 Patented Apr. 9, 1963 acids such as acetic acid, trimethyl acetic acid, propionic acid, 4,4-dimethyl pentanoic acid, IO-undecenoic acid; cycloalkyl-alkanoic acids such as fi-cyclopentyl propionic acid; aryl alkanoic acids such as phenyl propionic acid; cycloalkanoic acids such as hexahydrobenzoic acid and hexahydroterephthalic acid; and phenyl carboxylic acids such as benzoic acid and 3,5-dinitrobenzoic acid.

One process for the preparation of compounds of Formula I comprises reacting a secondary amine having the formula \NH Rf. (II) wherein R and R are lower alkyl and when taken together with the nitrogen atom are selected from the group consisting of pyrrolidino, piperidyl and morpholino with a compound having the formula U-OR wherein R, R and R have the above definition, h' drolyzing the latter a short time with a weak lower alkanoic acid such as acetic acid or propionic-acid to form a 17;?- oxygenated A -estradiene-3-one of Formula I and recovering the latter. The compounds of Formula I may then be isomerized with strong mineral acids to form 13 -estradiene-l7fi ol-3-one or its esters.

Another process for the preparation of the estradienes of Formula I comprises reacting a compound of the formula JOB wherein R has the above definition, prepared according to copending U.S. application Serial No. 57,136, now U.S. Patent No. 3,056,811, with a secondary amine of Formula II to form the corresponding 3-enamino-17fl-oxygenated- A -estratriene of Formula IV, hydrolyzing the latter a short time with a weak alkanoic acid to form the corresponding 17fl-oxygenated-A -estradiene- 3-one of Formula I and recovering the latter.

The improved process for the preparation of l7fl-oxygenated-A -estradiene-3-ones of Formula V com-- TABLEI N 35 W \jnm /\\UOR n l I wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms and R and R may be lower alkyl and when taken together are selected from the group consisting of pyrrolidyl, piperidyl and morphol-ino.

The compounds of Formula III are 3-methyl-7-oxo-8- (3'oxobutyl) -3,4-(3'-oxygenated 1'-2' cyclopentano)- A -octahydronaphthalenes and may be prepared as described in commonly-assigned, copending application Serial No. 36,171, filed June 15, 1960, now US. Patent No. 3,019,252.

In the following examples there preferred embodiments to illustrate ever, it should are described several the invention. Howbe understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE I Preparation of 17p-Benzoyloxy-A -Estradiene- 3-0ne STEP A.PREPARATION OF 17 fi-BENZOYLOXY-ii- PYRROLIDINO-A -ESTRATRIENE There was heated to the boiling point for a period of 4 minutes a mixture of 10 cc. of pure methanol, 1 gm. of 3/3-methyl 7 oxo-8B-(3' oxobutyD-3 a,4/8-(3-benzoyloxy-'1,2'-cyclopentano) -octahydronaphthalene and 1 cc. of pyrrolidine. The reaction was allowed to remain overnight at room temperature and cooled for about 1 more hour in a refrigerator before vacuum filtering. After vacuum filtering, washing with iced methanol and drying, 980 mg. (being a yield of 90%) of l7f3-benzoyloxy-3-pyrrolidino-A -estratriene were obtained, sufficiently pure for its use in Step B.

For analysis, the product was recrystallized by dissolution in lukewarm benzene and methanol added thereto. After drying, the product had a melting point of 148 C. and a specific rotation [a] =+261T (c.==0.72% in benzene).

was dissolved in 30 cc. of acetic acid The ultraviolet spectra determined in ether showed: 228 m (e=26,500). Others A at 273, 280 and 297 mi, and 1 348 ma e=23,000)

The clear yellow product was soluble in 3 volumes of lukewarm benzene, slightly soluble in methanol and in ether.

Analysis.C I-I O N: molecular Calculated: C, 81.07%; H, 8.21%; C, 80.9%; H, 8.2%; N, 3.2%.

This compound is not described in the literature.

STEP B.PREPARATION OF 17B-BENZOYLOXY-A ESTRADIENE-3-ONE (a) 0.68 of the compound prepared in Step A were dissolved in 0.68 cc. of pure acetic acid under agitation as rapidly as possible. After the product was dissolved, 6.8 cc. of distilled water were immediately added. Crystallization of 17fl-benzoyloxy-A -estradiene 3 one commenced very soon. The mixture was allowed to stand for a quarter of an hour at room temperature and the precipitate formed was vacuum filtered, washed with water and dried. The raw precipitate obtained was purified by recrystallization from boiling acetone. The product had a melting point of 173-174" C., and a specific rotation [a] =+106.4 (c.= l% in chloroform). A second recrystallization from acetone or isopropyl ether' did not change the melting point.

The ultra violet spectra determined in ethanol shows: a 234 m (e=31,550), A 280 m (6 920)- The product was soluble in Warm acetone and in warm isopropyl ether, and insoluble in water.

Its infrared spectra confirmed the asbence of conjugated ketone function and the presence of the benzoate function.

weight=429.5 8. N, 3.26% Found:

Analysis.--C H O molecular weight=376.5. Calculated: C, 79.75%; H, 7.5%. Found: C, 79.5%; H, 7.6%.

This compound is not described in the literature.

A -estradiene-l7fl-ol-3-one is obtained by the same suite of reactions.

7 EXAMPLE II Preparation of 17fi-Benz0yl0xy-A -Estradiene-S-One resented 50 mg. (an 8% yield) of 17fi-benzoyloxy- A -estradiene-one.

The filtration liquors and the wash liquor were combined and brought to a pH of 9 by slow addition of sodium hydroxide solution under agitation. An abundant precipitate was formed which was vacuum filtered, washed with water and dried. 530 mg. (a yield of 87%) of 17pbenzoyloxy-A -estradiene-3-one were obtained which was purified by recrystallization from acetone. The product had a melting point of l63164 C., and did not give a depression of the melting point when mixed with 175- benzoyloxy-A -estradiene 3 one obtained starting from 17-benzoyloxy-19-nor-A -androstene-5-ol-3-one.

By heating with methanolic pyrrolidine, 17fl-benzoyloxy A estradiene-S-one furnished 17p -benzoyloxy-3-pyrrolidino-A -estratriene described in Step 1 of the example.

EXAMPLE III lsomerizatian of 17p-Benz0yloxy-A -Estradiene- 3-0ne Into 17B-Benz0yl0xy-A -Estradiene-3-0ne 1 gm. of 17fi-benzoyloxy-A -estradiene-3-one containing 10% of perchloric acid (27 cc. of acetic acid plus 3 cc. of 63% perchloric acid) and the solution was allowed to stand for a period of 30 minutes at a temperature of 25 C. After the addition of 300 cc. of water, a gummy prodnot was obtained which was extracted three times with 50 cc. of methylene chloride. The organic phases were combined, washed with 20 cc. of a saturated solution of sodium bicarbonate then twice with 100 cc. of water until the wash watens were neutral. The product remaining was dried. A gum was obtained which was made to crystallize by the addition of 2 cc. of isopropyl ether. The solution was cooled 15 minutes and vacuum filtered. The precipitate was washed twice with 2 cc. of cold isopropyl ether. 17B-benzoyloxyl-A -estradiene-3- one melting at 163-1 64 C. was obtained with an almost quantitative yield.

The present application is a divisional application of application Serial No. 124,317, filed July 17, 1961, now United States Patent No. 3,052,672.

Various modifications of the processes of the present invention may be made without departing from the spirit or scope thereof, and it is to be understood that the invention be limited only as defined in the appended claims.

We claim:

1. A process for the preparation of a Nil-oxygenated- A -estradiene-3-one having the formula di-lower alkyl amines, pyrrolidine, piperidine and morpholine with a 17,9-oxygenated-A -estradiene-3-one having the formula a if to wherein R has the above definition to form the corresponding 3 enamino oxygenated-A estratriene having the formula V wherein the lower allcanoic References Cited in the file of this patent UNITED STATES PATENTS 3,052,672 Nomine et a1. Sept. 4, 1962 

1. A PROCESS FOR THE PREPARATION OF A 17B-OXYGENATED$5(10),9(11)-ESTRADIENE-3-ONE HAVING THE FORMULA 